Critics submitted their response to the draft guidance, titled “Commercially Distributed In Vitro Diagnostic Products Labeled for Research Use Only or Investigational Use Only: Frequently Asked Questions” in written comments to the FDA. The guidance was released in June, and the 90-day comment period expired August 30.

“We are working to finalize, but we don’t expect it to be anytime soon,” FDA spokeswoman Erica Jefferson told GEN. “We received a lot of feedback.”

FDA has argued that the new rules are needed in order to stop companies from getting around its medical device review process for the commercialization of diagnostics. The industry contends that the proposed changes would instead lead to regulations that disrupt the operations of clinical molecular labs.

The agency explained that the draft guidance emerged after the agency noticed an increase in products being marketed in ways that suggest they had clinical use, even though the products were labeled for research use only. David L. Rosen, a partner and co-chair of the life sciences industry team at the law firm Foley & Lardner LLP, told GEN that clients are concerned about what products they can sell as RUO/IUO tests and what they can’t under FDA’s proposed guidelines. “We need research, but we also need to make sure that people don’t rely on tests that aren’t verified and validated.”

Joseph Panetta, president and CEO of BIOCOM, explained to GEN that its message to the FDA is “let’s balance the compliance and the policing with a more positive look at how we can promote innovation. We really need more open dialogue between the industry and the FDA, and the FDA appears to be more and more in compliance mode rather than taking a look at how to promote innovation.” Panetta’s arguments were echoed by most of the 55 groups and individuals that submitted comments to FDA.

Comments to FDA

The Biotechnology Industry Organization (BIO) raised issue with FDA’s definition of “research use” to mean “evaluate design, limited-scale performance, and issues such as usability of the test.” BIO has said that the definition is overly narrow and contrasted it to FDA’s 2007 ASR (analyte-specific reagents) Guidance, which includes in the definition evaluating potential clinical or informational usefulness of the test.

“BIO is concerned that the draft guidance lacks adequate clarity for implementation, and believes that certain provisions are inappropriate and inconsistent with applicable law and historic FDA practice,” Paul Sheives, director, diagnostics and personalized medicine policy for BIO, told the FDA.

He said that if the agency insisted on moving forward with new RUO and IUO rules, “FDA should proceed in a phased-in manner to allow time for companies to submit the required regulatory submissions to ensure that access to many important research tools and continued patient access to important clinical diagnostic information is not blocked.”

The Association for Molecular Pathology (AMP) said its members expressed fear that the guidance may prompt many manufacturers to avoid FDA review by withdrawing RUOs from the clinical market altogether. “This has already occurred for many analytes, from blood-borne pathogens to sexually transmitted diseases. This would then create a shortage of supplies to develop laboratory tests, resulting in a scarcity of tests and ultimately barriers for patients’ access to medically necessary tests,” Elaine Lyon, Ph.D., chair of AMP’s Professional Relations Committee, said in the group’s comment to FDA.

A Merck & Co. executive told FDA the draft guidance also affects drug and biologics manufacturers, which make extensive use of IVD tests in R&D. “We urge the agency to draft a separate guidance document(s) to address use of RUO or IUO diagnostic tests in drug and biologic R&D activities as well as how the current guidance might affect a manufacturer using an RUO or IUO diagnostic test that subsequently could be regarded as misbranded,” Ekopimo Ibia, Merck’s director and U.S. regulatory policy lead, told the FDA.

Manufacturers Becoming Regulators

BIO also faulted the agency for expanding its definition of “intended use” beyond manufacturers to include the acts of RUO/IUO product users. The organization criticized the draft guidance for ordering a manufacturer to halt sales of its products to a customer if it knows “or has reason to know” that laboratory customers are using an RUO/IUO IVDs for a clinical diagnostic or patient-management purpose.

Panetta noted that FDA’s reason-to-know standard puts companies in the awkward position of policing their customers, creating an adversarial relationship that will hurt sales. “There’s a certain relationship that exists between a supplier and a customer, and once you cross that line and are viewed by your customers as being suspicious of their practices, you really damage the relationship between supplier and customer,” Panetta pointed out. IVD manufacturers, he added, “shouldn’t have to be acting as compliance officers and police officers and detectives relative to their customers.”

Johns Hopkins University (JHU) told FDA it identified “well over 100 products used in dozens of validated lab-developed tests (LDTs) that they would potentially no longer be able to obtain” if the draft guidance were to be finalized into new regulations. “This will have an enormous impact on the kinds of information we are able to provide to physicians caring for the often very complicated patients seen here,” wrote Michael J. Borowitz, M.D., Ph.D., JHU’s deputy director for clinical affairs.

Dr. Borowitz said JHU would be unable to provide clinicians with laboratory services including: diagnosis of HIV infection in infants of infected mothers and of almost any prenatal or postnatal inherited abnormality; assessment of various mutations in cancers; determination of bone marrow engraftment after stem cell transplantation; diagnosis of thrombotic thrombocytopenic purpura and neurodegenerative disorders; therapeutic drug monitoring; and identification of some unusual microorganisms like viruses causing meningitis.

“Demonstrating that a new test is both analytically and clinically valid and showing that its performance characteristics are monitored periodically through a program of proficiency testing should be the criteria for considering a test acceptable,” Dr. Borowitz added.

Potential Solutions

The American Society of Hematologists (ASH) recommended that FDA enhance the inspection of clinical labs under the Clinical Laboratory Improvement Amendments (CLIA) of 1988 rather than focus on product labeling.

“Novel mutations are being identified regularly, and there is significant research suggesting that many of these are not far from being valuable measurements in the clinic,” ASH President J. Evan Sadler, M.D., Ph.D., told the FDA. “All of these assays are performed with RUO products. The costs associated with bringing each of these reagents to approval following the usual FDA premarket pathway are simply too high to make rational business sense for manufacturers.”

The American Clinical Laboratory Association and Life Technologies noted that CLIA was written to permit labs to use RUO and IUO products without obtaining explicit FDA say-so as long as the lab established performance standards for the test and that test was validated.

Two subsidiaries of Quest Diagnostics suggested that FDA allow for more products to qualify as ASRs by broadening the definition to include products that are simply a combination of ASRs and that are manufactured in accordance with Quality System Regulations (QSR). Celera and Focus Diagnostics argued that it would encourage manufacturers who now label the reagents as RUOs or IUOs to register and list the expanded ASRs with the FDA, especially if many of the reagents could qualify as Class 1 exempt products.

“Clinical laboratories that employ these reagents in LDTs validated pursuant to CLIA could then use the ASR disclaimer on their report to healthcare professionals. We believe this solution is the least burdensome approach, especially if done in accordance with a grace period,” James M. McNally, Ph.D., vp, diagnostic products for Quest Diagnostics. That grace period should stretch at least three years, he added.

Expanding the ASR definition was also suggested by the AMP: “Accommodations should be made to enable certain reagents such as primer or probe mixes to be sold as ASRs. Alternatively, another regulatory pathway could be designed for products that are too complex to qualify as ASRs but are not full test kits or test systems.”

Weighing Risk and Benefit

An umbrella group that says it represents labs performing approximately half of all lab-based urine drug testing for chronic pain management in the U.S. contends that the draft guidance is unnecessary. “We are deeply concerned that if this guidance were implemented, it would place unnecessary burdens on clinical labs, exceed FDA statutory authority and legal precedent, and ultimately constrain patients’ access to medically necessary diagnostic services with no improvement in safety,” the Coalition for Excellence in Medication Monitoring (CEMM) declared in an August 30 letter to FDA.

In a footnote, CEMM added: “There has not been any demonstration that the existing regulatory structure does not adequately protect public health. Any additional regulatory oversight should recognize the unique nature of LDTs, their role in patient care, and the need to foster innovation for patient benefit. Any such regulatory approach should be risk based utilizing least burdensome provisions.”

Industry arguments about the drawbacks of regulation have not always carried the day in the current era of a risk averse FDA. In the case of RUO and IUO products, however, they seem to have at least been effective in staving off quick action, judging from FDA’s comment that no final guidance is expected soon.

Ideally, FDA will use the time to amend its guidance and accommodate at least some industry concerns. The agency should consider limiting manufacturer liability for the use of RUOs and IUOs by customers and give companies sufficient time to implement new regulations.

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